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Comment
. 2023 Aug 1;80(8):787-795.
doi: 10.1001/jamapsychiatry.2023.1321.

Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms

Joeffre Braga  1   2   3 , Mariel Lepra  1   2   3 , Stephen J Kish  1   2   3   4 , Pablo M Rusjan  5   6 , Zahra Nasser  1 , Natasha Verhoeff  1 , Neil Vasdev  1   2   4 , Michael Bagby  2   7 , Isabelle Boileau  1   2   3   4 , M Ishrat Husain  1   2   3   4 , Nathan Kolla  1   2   3   4   8 , Armando Garcia  1   2 , Thomas Chao  9 , Romina Mizrahi  5   6 , Khunsa Faiz  10 , Erica L Vieira  1   2 , Jeffrey H Meyer  1   2   3   4
Affiliations
Comment

Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms

Joeffre Braga et al. JAMA Psychiatry. .

Abstract

Importance: Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.

Objective: To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.

Design, setting, and participants: This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.

Main outcomes and measures: The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.

Results: The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, -0.53; 95% CI, -0.79 to -0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).

Conclusions and relevance: In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Vasdev, Boileau, and Meyer reported receiving salary support from their respective Canada Research Chair awards. Dr Husain reported receiving grants from Compass Pathways; holding stock options for advisory board services from Mindset Pharma; serving as a consultant for Psyched Therapeutics and Wake Network outside the submitted work; and receiving salary support from an Academic Scholars Award from the Department of Psychiatry, University of Toronto. Dr Kolla reported receiving salary support from a Waypoint/University of Toronto Research Chair in Forensic Mental Health Science. Prof Meyer reported receiving grants from Sanofi outside the submitted work; potentially receiving contracts, which may include salary support, from Bristol Myers Squibb and AbbVie; holding stock in Moderna; being an inventor on patents for a dietary supplement to prevent postpartum sadness; and being an inventor on submitted patents for some blood markers to predict inflammation in psychiatric illness; in addition, there is an agreement in development with Exceltis to distribute the dietary supplement, which may lead to funding. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Translocator Protein Total Distribution Volume (TSPO VT) in Brain Regions of Interest in Persons With COVID-19 Disease and Depression With or Without Other Cognitive Symptoms (COVID-DC) vs Healthy Persons
Closed triangles represent high-affinity binders; open triangles, mixed-affinity binders (MAB); dark blue symbols, 20 persons with COVID-DC; light blue symbols, 20 healthy persons; horizontal orange lines, group means. After correcting for genotype effect by multiplying MAB TSPO VT by a factor of 1.4, nonparametric comparison with the Mann-Whitney U test yielded similar levels of statistical significance (ventral striatum, U = 117, P = .02; dorsal putamen, U = 121, P = .03; hippocampus, U = 156, P = .24; prefrontal cortex, U = 164, P = .34; anterior cingulate cortex, U = 143, P = .13).
Figure 2.
Figure 2.. Pearson Correlation Between Translocator Protein Total Distribution Volume (TSPO VT) in the Dorsal Putamen and Motor Speed
A, Negative correlation between TSPO VT in dorsal putamen and T-score on a finger-tapping test with the dominant hand in 19 persons with COVID-19 illness and depression with or without other cognitive symptoms (COVID-DC). B, Comparison of TSPO VT in dorsal putamen of 10 participants with COVID-DC with the slowest tapping rate with their dominant hand vs 20 healthy persons. C, Negative correlation between TSPO VT in dorsal putamen with T-score on a finger-tapping test with the nondominant hand in 18 persons with COVID-DC. D, Comparison of TSPO VT in dorsal putamen of 10 persons with COVID-DC with the slowest tapping with their nondominant hand vs 20 healthy persons. For all panels, TSPO VT of mixed-affinity binders (n = 4 total) is multiplied by 1.4 to adjust for rs6971 genotype effect on radiotracer binding. Horizontal orange lines represent group means; closed triangles, high-affinity binders; open triangles, mixed-affinity binders; dark-blue symbols, persons with COVID-DC; light-blue symbols, healthy persons. MD indicates mean difference.
Figure 3.
Figure 3.. Theoretical Implications of Dorsal Putamen (DP) And Ventral Striatum (VS) Gliosis
ACE2 indicates angiotensin-converting enzyme 2.
See this image and copyright information in PMC

Comment in

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